This invention relates generally to the field of neurobiology and more specifically to a novel neuronal cell growth factor, polynucleotides encoding the factor, and methods of use.
The mature central nervous system exhibits the capacity to alter cellular interactions as a function of the activity of specific neuronal circuits. This capacity is believed to underlie learning and memory as well as aspects of postnatal development of the brain (Schatz, C., Neuron, 5:745, 1990). Cellular mechanisms underlying activity-dependent plasticity are known to be initiated by rapid, transmitter-induced changes in membrane conductance properties and activation of intracellular signaling pathways (Bliss and Collingridge, Nature, 361:31, 1993). Several lines of evidence also indicate a role for rapid synthesis of mRNA and protein in long-term neuroplasticity. For example, classical studies of learning and memory demonstrate a requirement for protein synthesis in a long-term, but not short-term memory (Flexner, ,et al., Science, 141:57, 1963; Agranoff, B., Basic Neurochemistry, 3rd Edition, 1981; Davis and Squire, Physiol. Bull., 96:518, 1984), and long-term enhancement of synaptic connectivity, studied in cultured invertebrate neurons (Montarolo, et al., Science, 234:1249, 1986; Bailey, et al., Neuron, 9:749, 1992) or in the rodent hippocampus (Frey, et al., Science, 260:1661, 1993; Nguyen, et al., Science, 265:1104, 1994), is blocked by inhibitors of either RNA or protein synthesis. Importantly, inhibitors of macromolecular synthesis are most effective when administered during a brief time window surrounding the conditioning stimulus indicating a special requirement for molecules that are rapidly induced (Goelet, et al., Nature, 322:419, 1986).
Immediate early genes (IEGs) are rapidly induced in neurons by neurotransmitter stimulation and synaptic activity and are hypothesized to be part of the macromolecular response required for long-term plasticity (Goelet, et al., supra; Sheng and Greenberg, Neuron, 4:477, 1990; Silva and Giese, Neurobiology, 4:413, 1994). To identify cellular mechanisms that may contribute to long-term plasticity in the vertebrate brain, differential cloning techniques have been used to identify genes that are rapidly induced by depolarizing stimuli (Nedivi, et al., Nature, 363:713, 1993; Qian, et al., Nature, 361:453, 1993; Yamagata, et al., Neuron, 11:371, 1993; Yamagata, et al., Learning and Memory 1:140, 1994; Yamagata, et al., Journal of biological Chemistry, 269:16333, 1994; Andreasson and Worley, Neuroscience, 69:781, 1995; Lyford, et al., Neuron, 14:433, 1995). In contrast to the earlier focus on transcription factors, many of the newly characterized IEGs represent molecules that can directly modify the function of cells and include growth factors (Nedivi, et al., supra; Anreasson and Worley, supra), secreted enzymes that can modify the extracellular matrix, such as tissue plasminogen activator (Qian, et al., supra ), enzymes involved in intracellular signaling, such as prostaglandin synthase (Yamagata, et al., supra), and a novel homolog of H-Ras, termed Rheb (Yamagata, et al., supra), as well as a novel cytoskeleton-associated protein, termed Arc (Lyford, et al., supra). The remarkable functional diversity of this set of rapid response genes is representative of the repertoire of cellular mechanisms that are likely to contribute to activity-dependent neuronal plasticity.
The present invention provides a novel neuronal growth factor. Narp, (neuronal-activity regulated pentraxin), which is highly potent in inducing enhanced growth of neuronal dendritic processes.
In a first embodiment, the invention provides Narp polypeptide and isolated polynucleotides encoding Narp.
In another embodiment, the invention provides a method for inducing growth of a neuronal cell by contacting the cell with an amount of Narp polypeptide or a Narp encoding polynucleotide (in operable linkage with appropriate transcription elements) effective for inducing growth of the neuron. Neuronal cell can be induced either in vitro or in vivo.
In another embodiment, the invention provides a method for inducing migration of a neuronal cell by contacting the cell with an amount of Narp polypeptide or a Narp encoding polynucleotide effective for inducing migration of the neuron.
In one aspect of the invention, diagnostic methods are provided including contact a sample suspected of containing Narp with either a nucleic acid or immunodiagnostic reagent.
In yet another embodiment, the invention provides a method for treating a subject having a neuronal cell disorder by administering to the subject a therapeutically effective amount of Narp polypeptide or Narp encoding polynucleotide. Such disorders may include stroke, cerebral palsy and various degenerative diseases, for example.